Individuals with intractable epilepsy have a ~1% annual risk of Sudden Unexpected Death in Epilepsy (SUDEP). Pre-mortem risk factors are unknown; however, evidence suggests autonomic nervous system (ANS) failure, sustained apnea/hypoxemia, or some combination of respiratory and cardiovascular (CV) collapse underlies the fatal event. Adverse ANS signs are prominent in epilepsy, with ANS-driven cardiac arrhythmias (bradycardia, asystole, tachyarrhythmias) in ~72% of epilepsy patients, hypotension, impaired baroreflex sensitivity (potentially compromising cerebral blood flow), enhanced sympathetic outflow, expressed as increased sweating and decreased inter-ictal nocturnal heart rate variability (HRV) common. EEG characteristics, including post-ictal generalized EEG suppression (PGES) is suggestive of high SUDEP-risk, strongly correlate with increased sweating and decreased HRV, and is typically accompanied by profound hypotension. Neural mechanisms underlying these patterns need to be defined. Our findings of damage to pulvinar thalamic CO2 and O2 integration areas, and to left insular parasympathetic regulatory structures in SUDEP victims suggest that an impaired ability to integrate respiratory sensory signals, combined with exaggerated parasympathetic action, inducing hypotension, thus resulting in cerebral hypoperfusion leading to the EEG signs of PGES, contribute to a fatal scenario. Deficits in other respiratory and ANS regulatory areas may participate, but those sites must be determined. We propose to relate focal brain structural changes in persons with epilepsy to particular peri-ictal autonomic and breathing patterns recognized as indices of risk for death. We found, in other syndromes exhibiting sudden death, e.g., heart failure, significant lateralized neural injury in brainstem and forebrain ANS and respiratory areas. Such unilateral injury can induce asymmetric ANS, and especially, sympathetic drive, establishing a scenario for potentially fatal arrhythmia or hypotension. We will determine peri-ictal physiological pattern of EEG, and especially PGES, blood pressure, HRV, baroreflex sensitivity, cardiac arrhythmia, and breathing that lead to risk of SUDEP, collect high resolution T1-weighted, diffusion tensor, and kurtosis images, and relate extent and laterality of injury to the physiological patterns. The studies will provide insights into mechanisms of failure in SUDEP, and suggest pre-mortem indications of characteristics that lead to a fatal scenario that are suitable for targeted intervention.